Hippo signaling promotes lung epithelial lineage commitment by curbing Fgf10 and β-catenin signaling

Volckaert, Thomas; Yuan, Tingting; Yuan, Jie; Boateng, Eistine; Hopkins, Seantel; Zhang, Jin‐San; Thannickal, Victor J.; Fässler, Reinhard; Langhe, Stijn P. De

doi:10.1242/dev.166454

Cited by 41 publications

(43 citation statements)

References 66 publications

(140 reference statements)

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“…Fgfr2 signaling distally around E15.5 is required for the lung to transition from a branching program into an alveolar differentiation program; as we have previously demonstrated that overexpression of Fgf10 starting from E15.5 onwards prevents this transition by inducing distal epithelial Fgfr2 signaling (Volckaert et al, 2013b;Volckaert et al, 2019). Upregulation of Fgfr2 in the proximal epithelium at this stage also coincides with the differentiation of the basal cell lineage (Volckaert et al, 2013b;Balasooriya et al, 2017;Volckaert et al, 2017;Volckaert et al, 2019).…”

Section: Fgfr1 and Fgfr2 Expression During Embryonic Lung Developmentmentioning

confidence: 71%

Temporospatial Expression of Fgfr1 and 2 During Lung Development, Homeostasis, and Regeneration

et al. 2020

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Fgfr1 (Fibroblast growth factor receptor 1) and Fgfr2 are dynamically expressed during lung development, homeostasis, and regeneration. Our current analysis indicates that Fgfr2 is expressed in distal epithelial progenitors AT2, AT1, club, and basal cells but not in ciliated or neuroendocrine cells during lung development and homeostasis. However, after injury, Fgfr2 becomes upregulated in neuroendocrine cells and distal club cells. Epithelial Fgfr1 expression is minimal throughout lung development, homeostasis, and regeneration. We further find both Fgfr1 and Fgfr2 strongly expressed in cartilage progenitors and airway smooth muscle cells during lung development, whereas Fgfr1 but not Fgfr2 was expressed in lipofibroblasts and vascular smooth muscle cells. In the adult lung, Fgfr1 and Fgfr2 were mostly downregulated in smooth muscle cells but became upregulated after injury. Fgfr1 remained expressed in mesenchymal alveolar niche cells or lipofibroblasts with lower levels of expression in their descendant (alveolar) myofibroblasts during alveologenesis.

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Section: Fgfr1 and Fgfr2 Expression During Embryonic Lung Developmentmentioning

confidence: 71%

Temporospatial Expression of Fgfr1 and 2 During Lung Development, Homeostasis, and Regeneration

et al. 2020

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“…Among epithelial cells, we discover a shift in epithelial cell population composition in the distal lung, from alveolar epithelial cells towards enrichment in 150 cell populations that typically reside in the airway. We identify the existence of aberrant basaloid Importantly, they express SOX9, a transcription factor critical to distal airway development, repair, also indicated in oncogenesis (19,20). Anatomically, these cells localize to a highly enigmatic region in the IPF lung, at the active edge of the myofibroblast foci.…”

Section: Discussionmentioning

confidence: 86%

“…These cells express markers of epithelial mesenchymal transition (EMT) such as VIM, CDH2, FN1, COL1A1, TNC, and HMGA2 (9, 10, 11 , 12), senescence related genes including CDKN1A, CDKN2A, CCND1, CCND2, MDM2, and GDF15 (13-15) ( Figure 2C, right) and the highest levels of established IPFrelated molecules, such as MMP7 (16), αVβ6 subunits (17) and EPHB2 (18). The cells exhibit 80 high levels and evidence for gene regulation by SOX9 ( Figure 2C upper panel), a transcription factor critical to distal airway development, repair, also indicated in oncogenesis (19,20). Aberrant basaloid cells were not detected in control lungs ( Fig.…”

Section: Resultsmentioning

confidence: 99%

“…They express EMT and senescence markers as well as molecules associated with IPF, and genes that are typically expressed in other organs. 175 Importantly, they express SOX9, a transcription factor critical to distal airway development, repair, also indicated in oncogenesis (19,20). Anatomically, these cells localize to a highly enigmatic region in the IPF lung, at the active edge of the myofibroblast foci.…”

Section: Discussionmentioning

confidence: 99%

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Single Cell RNA-seq reveals ectopic and aberrant lung resident cell populations in Idiopathic Pulmonary Fibrosis

Adams

Schupp

Poli

et al. 2019

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247

499

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We provide a single cell atlas of Idiopathic Pulmonary Fibrosis (IPF), a fatal interstitial lung disease, focusing on resident lung cell populations. By profiling 312,928 cells from 32 IPF, 29 healthy control and 18 chronic obstructive pulmonary disease (COPD) lungs, we demonstrate that IPF is characterized by changes in discrete subpopulations of cells in the three major parenchymal compartments: the epithelium, endothelium and stroma. Among epithelial cells, we identify a novel population of IPF enriched aberrant basaloid cells that co-express basal epithelial markers, mesenchymal markers, senescence markers, developmental transcription factors and are located at the edge of myofibroblast foci in the IPF lung. Among vascular endothelial cells in the in IPF lung parenchyma we identify an expanded cell population transcriptomically identical to vascular endothelial cells normally restricted to the bronchial circulation. We confirm the presence of both populations by immunohistochemistry and independent datasets. Among stromal cells we identify fibroblasts and myofibroblasts in both control and IPF lungs and leverage manifold-based algorithms diffusion maps and diffusion pseudotime to infer the origins of the activated IPF myofibroblast. Our work provides a comprehensive catalogue of the aberrant cellular transcriptional programs in IPF, demonstrates a new framework for analyzing complex disease with scRNAseq, and provides the largest lung disease single-cell atlas to date.

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“…Mammalian lung is a complex, stereotypically branched organ, whose development is strictly regulated by multiple signaling pathways. They include fibroblast growth factor (FGF) (Lebeche et al, 1999; Ohuchi et al, 2000; Tichelaar et al, 2000; del Moral et al, 2006; Cardoso and Lü, 2006), WNT (Shu et al, 2005a; Yin et al, 2008), bone morphogenetic protein (Weaver et al, 1999; Lu et al, 2001; Shu et al, 2005b), Sonic Hedgehog (Miller et al, 2004; White et al, 2006), epidermal growth factor (EGF) (Kheradmand et al, 2002), retinoic acid (Malpel et al, 2000), and HIPPO (Volckaert et al, 2019) pathways. Tight interplay of these pathways is essential also for lung epithelial homeostasis, regeneration, and repair (Volckaert and De Langhe, 2015; Volckaert et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

3D cell culture models demonstrate a role for FGF and WNT signaling in regulation of lung epithelial cell fate and morphogenesis

Rabata

Fedr

Souček

et al. 2020

Preprint

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15FGF signaling plays an essential role in lung development, homeostasis, and regeneration. Several 16 FGF ligands were detected in the developing lungs, however, their roles have not been fully elucidated. 17 We employed mouse 3D cell culture models and imaging to ex vivo study of a) the role of FGF ligands 18 in lung epithelial morphogenesis and b) the interplay of FGF signaling with epithelial growth factor 19 (EGF) and WNT signaling pathways. In non-adherent conditions, FGF signaling promoted formation 20 of lungospheres from lung epithelial stem/progenitor cells (LSPCs). Based on their architecture, we 21 defined three distinct phenotypes of lungospheres. Ultrastructural and immunohistochemical analyses 22 showed that LSPCs produced more differentiated lung cell progeny. In 3D extracellular matrix, FGF2, 23 FGF7, FGF9, and FGF10 promoted lung organoid formation with similar efficiency. However, FGF9 24 showed reduced capacity to promote lung organoid formation, suggesting that FGF9 has a reduced 25 ability to sustain LSPCs survival and/or initial divisions. Analysis of lung organoid phenotypes 26 revealed that FGF7 and FGF10 produce bigger organoids and induce organoid branching with higher 27 frequency than FGF2 and FGF9. Higher FGF concentration and/or the use of FGF2 with increased 28 stability and affinity to FGF receptors both increased lung organoid and lungosphere formation 29 efficiency, respectively, suggesting that the level of FGF signaling is a crucial driver of LSPC survival 30 and differentiation, and also lung epithelial morphogenesis. EGF signaling played a supportive but 31 nonessential role in FGF-induced lung organoid formation. Moreover, analysis of tissue architecture 32 and cell type composition confirmed that the lung organoids contained alveolar-like regions with cells 33 expressing alveolar type I and type II cell markers, as well as airway-like structures with club cells and 34 ciliated cells. WNT signaling enhanced the efficiency of lung organoid formation, but in the absence 35 of FGF10 signaling, the organoids displayed limited branching and less differentiated phenotype. In 36 summary, we present lung 3D cell culture models as useful tools to study the role and interplay of 37 signaling pathways in lung development and we reveal roles for FGF ligands in regulation of mouse 38 lung morphogenesis ex vivo. 39 65 amplification of Fgf10 expressing airway smooth muscle cell progenitors in the distal mesenchyme 66 (Volckaert and De Langhe, 2015). In adult lung, FGF10 and WNT signaling regulate the activity of 67 basal cells, the lung epithelial stem/progenitor cells (LSPCs) that ensure lung epithelial homeostasis 68 and repair after injury (Volckaert et al., 2013). However, the exact functions of FGF and WNT 69 signaling in LSPCs have not been fully elucidated. 70In this study, we investigated the role of FGF and WNT signaling in regulation of epithelial 71 morphogenesis from LSPCs. To this end, we developed and used several 3D cell culture techniques, 72 including lungosphere an...

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Hippo signaling promotes lung epithelial lineage commitment by curbing Fgf10 and β-catenin signaling

Cited by 41 publications

References 66 publications

Temporospatial Expression of Fgfr1 and 2 During Lung Development, Homeostasis, and Regeneration

Temporospatial Expression of Fgfr1 and 2 During Lung Development, Homeostasis, and Regeneration

Single Cell RNA-seq reveals ectopic and aberrant lung resident cell populations in Idiopathic Pulmonary Fibrosis

3D cell culture models demonstrate a role for FGF and WNT signaling in regulation of lung epithelial cell fate and morphogenesis

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